This project continues to have two long-term, interrelated objectives: (a) to define the mechanisms by which Leishmania donovani (LD) successfully parasitizes the tissue macrophage and thus causes persistent visceral infection, and in parallel, (b) to determine what endogenous T cell-dependent mechanisms (or exogenous immune products) are available to the host to enable it to control and eradicate this intracellular pathogen. These two objectives, whose ultimate intent is to improve the treatment of patients with visceral leishmaniasis (VL), require focusing not only the protozoan, its target cell (the macrophage). and the T cell, but also on their interaction at multiple levels-in vitro, in the tissue, and in the intact host. To extend our analysis of the key immunopathogenic mechanisms in VL, our specific aims are to: (1) determine the mechanisms of production of leishmanial antigen-specific interferon-gamma (IFN-gamma) and interleukin 2 (IL2); (2) characterize the role of il2 in experimental VL; (3) determine the role of the sensitized LYT-2+ cell in experimental VL; (4) examine the antileishmanial and tissue effects of six selected cytokines: tumor necrosis factor, interleukin 1, granulocyte-macrophage colony stimulating factor, macrophage-colony stimulating factor, interleukin 3, and interleukin 4; (5) extend our analysis of the LD- provoked tissue granuloma to the influxing mononuclear phagocyte, in situ expression of and requirement for soluble immune/inflammatory products, the effect of suppressor mechanisms, and the basis of defective granuloma formation in LD-infected C57BL/6-ep/ep mice; (6) characterize the immunologic maintenance of resistance in experimental VL, and (7) determine if the treatment of experimental VL can be enhanced by selected immunotherapeutic agents (IFN-gamma, IL2, cytokines in Aim 4 which prove effective) (a) using in alone. (b) synergistically with conventional chemotherapy (Pentostam), or (c) combination with antisuppressor treatments with or without Pentostam. We anticipate that the proposed detailed analysis, to be conducted at the cellular, tissue, and intact host levels, will provide a rationale basis for approaching the future pharmacologic/immunologic management of world-wide infections caused by L. donovani and other strains of Leishmania.